Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A.

Abstract	In mammals, methionine metabolism occurs mainly in the liver via methionine adenosyltransferase-catalyzed conversion to S-adenosylmethionine. Of the two genes that encode methionine adenosyltransferase(MAT1Aand MAT2A), MAT1A is mainly expressed in adult liver whereas MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic S-adenosylmethionine content and hyperplasia and spontaneously develop nonalcoholic steatohepatitis. In this study, we examined whether chronic hepatic S-adenosylmethionine deficiency generates oxidative stress and predisposes to injury and malignant transformation. Differential gene expression in MAT1A knockout mice was analyzed following the criteria of the Gene Ontology Consortium. Susceptibility of MAT1A knockout mice to CCl4-induced hepatotoxicity and malignant transformation was determined in 3- and 18-month-old mice, respectively. Analysis of gene expression profiles revealed an abnormal expression of genes involved in the metabolism of lipids and carbohydrates in MAT1A knockout mice, a situation that is reminiscent of that found in diabetes, obesity, and other conditions associated with nonalcoholic steatohepatitis. This aberrant expression of metabolic genes in the knockout mice was associated with hyperglycemia, increased hepatic CYP2E1 and UCP2 expression and triglyceride levels, and reduced hepatic glutathione content. The knockout animals have increased lipid peroxidation and enhanced sensitivity to CCl4-induced liver damage, which was largely due to increased CYP2E1 expression because diallyl sulfide, an inhibitor of CYP2E1, prevented CCl4-induced liver injury. Hepatocellular carcinoma developed in more than half of the knockout mice by 18 months of age. Taken together, our findings define a critical role for S-adenosylmethionine in maintaining normal hepatic function and tumorigenesis of the liver.
Authors	Maria L Martínez-Chantar, Fernando J Corrales, L Alfonso Martínez-Cruz, Elena R García-Trevijano, Zong-Zhi Huang, Lixin Chen, Gary Kanel, Matías A Avila, José M Mato, Shelly C Lu
Journal	FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 16 Issue 10 Pg. 1292-4 (Aug 2002) ISSN: 1530-6860 [Electronic] United States
PMID	12060674 (Publication Type: Journal Article)
Chemical References	Ion Channels Membrane Transport Proteins Mitochondrial Proteins Proteins RNA, Messenger Ucp2 protein, mouse Uncoupling Protein 2 S-Adenosylmethionine Carbon Tetrachloride Cytochrome P-450 CYP2E1 Methionine Adenosyltransferase
Topics	Animals Carbon Tetrachloride Chemical and Drug Induced Liver Injury Cytochrome P-450 CYP2E1 (genetics, metabolism) Diabetes Mellitus (genetics, metabolism) Disease Susceptibility Gene Expression Profiling Hepatitis, Animal (etiology, genetics, metabolism) Ion Channels Liver (metabolism) Liver Diseases (enzymology) Liver Neoplasms, Experimental (etiology, pathology) Membrane Transport Proteins Methionine Adenosyltransferase (genetics, physiology) Mice Mice, Knockout Mitochondrial Proteins Models, Biological Obesity (genetics, metabolism) Oxidative Stress Protein Biosynthesis Proteins (genetics) RNA, Messenger (biosynthesis) S-Adenosylmethionine (deficiency) Uncoupling Protein 2

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